Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine
Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine
复制标题
DOI：
10.1007/s00262-009-0811-7
复制
发表时间：
2010-06-01
影响因子：
5.8
通讯作者：
Hawkins, Robert
中科院分区：
文献类型：
--
作者：
Dangoor, Adam;Lorigan, Paul;Hawkins, Robert
在晚期转移性黑色素瘤中评价了多表位疫苗的增加剂量和不同方案的安全性和细胞免疫原性。该疫苗由质粒DNA和重组修饰的安卡拉牛痘病毒（MVA）组成，两者都表达来自五种黑色素瘤抗原的七个HLA.A2/A1表位串（Mel 3）。入组了41名HLA-A2阳性的III/IV期黑色素瘤患者。患者组接受一个或两个剂量的DNA. Mel 3，然后接受递增剂量的MVA. Mel 3。然后在没有疾病进展的情况下继续免疫接种8周。使用离体四聚体和IFN-γ ELISPOT测定法评价表位特异性CD 8 + T细胞应答。通过四聚体测定法检测，初免-加强DNA/MVA在22/31（71%）患者中诱导了Melan-A特异性CD 8 + T细胞应答。ELISPOT在10/31（32%）患者中检测到对至少一种表位的应答。低剂量DNA/MVA或单独MVA的T细胞应答率< 50%，高剂量DNA/MVA的T细胞应答率上升至91%。在8例显示临床获益证据的患者中，1例PR（24个月+），5例SD（5个月+）和2例混合应答，7例有相关免疫应答。与非免疫相比，Melan-A-四聚体+免疫与至进展时间的中位数增加8周（P = 0.037）和生存期增加71周（P = 0.0002）相关。高剂量疫苗耐受性良好。唯一显著的毒性是流感样症状和注射部位反应。DNA. Mel 3和MVA. Mel 3在初免-加强方案中产生对黑色素瘤抗原表位的高比率免疫应答。治疗耐受性良好，免疫应答与患者结局的相关性鼓励进一步研究。
Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens.Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-gamma ELISPOT assays. Safety and clinical responses were monitored.Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were < 50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions.DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation.